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| United States Patent |
5,053,424
|
|
Marzi
, et al.
|
October 1, 1991
|
2-(N-acyl)amino-6,7-dimethoxy tetralines, and pharmaceutical
compositions having antihypertensive activity containing same
Abstract
2-(N-acyl)amino-6,7-dimethoxy tetraline of general formula (I)
##STR1##
wherein R is selected from hydrogen and ethyl and A is an aminoacyl or
dipeptidyl radical are endowed with potent anti-hypertensive activity.
| Inventors:
|
Marzi; Mauro (Rome, IT);
Tinti; Maria O. (Rome, IT);
Pacifici; Licia (Rome, IT);
Franceschelli; Carla (Rome, IT);
Castorina; Massimo (Rome, IT)
|
| Assignee:
|
Sigma-Tau Industrie Farmaceutiche Riunite S.p.A. (Rome, IT)
|
| Appl. No.:
|
559052 |
| Filed:
|
July 30, 1990 |
Foreign Application Priority Data
| Jul 31, 1989[IT] | 48254 A/89 |
| Current U.S. Class: |
514/419; 514/563; 548/496; 562/443; 562/448; 562/450 |
| Intern'l Class: |
C07D 209/20; C07D 233/39; A61K 031/405; A61K 031/16 |
| Field of Search: |
548/496
562/443,448,450
514/419,563
|
References Cited
| Foreign Patent Documents |
| 1261855 | Sep., 1989 | CA | 548/496.
|
Primary Examiner: Springer; David B.
Attorney, Agent or Firm: Oblon, Spivak, McClelland, Maier & Neustadt
Claims
What is claimed is:
1. A compound of formula (I)
##STR51##
wherein R is selected from hydrogen and ethyl and A is an aminoacyl
radical selected from glycyl, methionyl, tryptophyl and tyrosyl, or a
dipeptidyl radical selected from leucylalanyl, tryptophylalanyl,
methionylalanyl and tyrosylalanyl.
2. As a compound of claim 1, 2-N-glycylamino-6,7-dimethoxy tetraline
hydrochloride.
3. As a compound of claim 1, 2-N-methionyl-amino-6,7-dimethoxy tetraline
hydrochloride.
4. As a compound of claim 1, 2-N-tryptophyl-amino-6,7-dimethoxy tetraline
hydrochloride.
5. As a compound of claim 1, 2-N-tyrosyl-amino-6,7-dimethoxy tetraline
hydrochloride.
6. As a compound of claim 1, 2-(N-leucylalanyl)amino-6,7-dimethoxy
tetraline hydrochloride.
7. As a compound of claim 1, 2-(N-tryptophylalanyl)amino-6,7-dimethoxy
tetraline hydrochloride.
8. As a compound of claim 1, 2-(N-methionylalanyl)amino-6,7-dimethoxy
hydrochloride.
9. As a compound of claim 1,
2-(N-ethyl,N-methionylalanyl)amino-6,7-dimethoxy tetraline hydrochloride.
10. As a compound of claim 1, 2-(N-ethyl,
N-tryptophylalanyl)amino-6,7-dimethoxy tetraline hydrochloride.
11. As a compound of claim 1, 2-(N-tyrosylalanyl)amino-6,7-dimethoxy
tetraline hydrochloride.
12. An orally or parenterally administrable pharmaceutical composition
comprising an amount of one of the compounds of formula I of claim 1
effective to bring about a pressure decrease in a hypertensive subject,
and a pharmacologically acceptable excipient.
13. The pharmaceutical composition of claim 12, in unit dosage form,
comprising from about 20 to about 50 mg of one of the compounds of formula
I.
Description
The present invention relates to 2-(N-acyl)amino-6,7-dimethoxy tetralines
having general formula (I)
##STR2##
wherein R is selected from hydrogen and ethyl and A is an aminoacyl or
dipeptidyl radical.
By "aminoacyl", the radicals glycyl, methionyl, tryptophyl and tyrosyl are
preferably meant.
By "dipeptidyl", the radicals leucylalanyl, tryptophylalanyl,
methionylalanyl and tyrosylalanyl are preferably meant.
The compounds of general formula (I) are endowed with potent
antihypertensive activity.
The present invention also relates to the process for producing the
compounds of general formula (I) and the pharmaceutical compositions which
comprise a compound of general formula (I) as active ingredient.
Tetraline derivatives loosely related to the compounds of the present
invention from a structural viewpoint are disclosed in UK patent 1,377,356
and in the European patent application 64964. However, in addition to
being different in structure, the known tetraline derivatives possess
pharmacological activities totally different from and unrelated to the
antihypertensive activity shown by the compounds of general formula (I).
In fact, the compounds of the British patent exhibit analgesic activity,
while the compounds disclosed and claimed in the European patent
application are active on the central nervous system and can be used for
the therapeutical treatment of psychopathias such as schizophrenia.
The compounds of general formula (I) can be prepared via konwn processes.
Synthesis of the compounds of general formula (I) wherein A is an
aminoacyl radical (hereinbelow, compounds I') and of the compounds wherein
A is a peptidyl radical (hereinbelow, compounds I") are briefly summarized
hereinbelow in the following reaction schemes.
Synthesis scheme for the compounds of general formula (I) wherein A is the
radical of an aminoacid.
##STR3##
wherein the meaning of R.sub.1 is described in table 1.
TABLE I
______________________________________
##STR4## I'
R.sub.1 Reference name
A
______________________________________
H ST 582 glycyl
CH.sub.2CH.sub.2SCH.sub.3
ST 581 methionyl
##STR5## ST 580 tryptophyl
##STR6## ST 589 tyrosyl
______________________________________
Synthesis scheme of the compounds of general formula (I) wherein A is the
radical of a dipeptide.
##STR7##
wherein the meaning of R and R.sub.2 is described in table 2.
TABLE 2
______________________________________
##STR8## I"
Refer-
ence
R.sub.2 R name A
______________________________________
##STR9## H ST 584 leucylalanyl
##STR10## H CH.sub.2 CH.sub.3
ST 585 ST 604
tryptophylalanyl tryptophylalanyl
CH.sub.3 SCH.sub.2CH.sub.2
H ST 586 methionylalanyl
CH.sub.2 CH.sub.3
ST 606 methionylalanyl
##STR11## H ST 605 tyrosylalanyl
______________________________________
EXAMPLE 1
Preparation of 2-N-glycylamino-6,7-dimethoxy tetraline hydrochloride (ST
582)
1st Step: Preparation of 2-(N-carbotertbutoxyglycyl)amino-6,7-dimethoxy
tetraline
2-amino-6,7-dimethoxy tetraline (0.4 g; 2.07 mmoles) was dissolved in 20 ml
CH.sub.2 Cl.sub.2. Dicyclohexylcarbodiimide (0.4 g; 2.07 mmoles) and
carbotertbutoxyglycine (0.36 g; 2.07 mmoles) were added to the solution.
The solution was kept under stirring for 2 hours. Dicyclohexylurea that
formed was then filtered off. The filtrate was extracted with a saturated
solution of NaHCO.sub.3, diluted HCl and H.sub.2 O till neutrality was
reached. The organic phase separated and dried was concentrated under
vacuum. The residue thus obtained was chromatographed on a silica gel
column, eluting with CHCl.sub.3 --AcOEt, 1:1.
The collected fractions gave 0.6 g of the title compound; yield 86%; M.P.
124.degree.-126.degree. C. crystallized from cyclohexane.
##STR12##
2nd Step: Preparation of 2-N-glycylamino-6,7-dimethoxy tetraline
hydrochloride
The compound of the preceding step (0.33 g; 0.9 mmoles) was treated with 2
ml formic acid for 30 minutes at room temperature. The mixture was taken
up with methylene chloride and extracted with H.sub.2 O and the acqueous
phase was neutralized with NaHCO.sub.3 and re-extracted with CH.sub.2
Cl.sub.2. The separated and dried organic phase was concentrated under
vacuum, thus furnishing 2-N-glycylamino-6,7-dimethoxy tetraline; M.P.
106.degree.-108.degree. C.; yield 62%.
The base thus obtained was dissolved in a saturated solution of HCl in
ethanol. 2-N-glycylamino-6,7-dimethoxy tetraline hydrochloride was
precipitated with ethyl ether and then crystallized with isopropanol; M.P.
225.degree.-228.degree. C.
##STR13##
EXAMPLES 2-4
Preparation of 2-N-methionylamino-6,7-dimethoxy tetraline hydrochloride (ST
581)
Preparation of 2-N-tryptophylamino-6,7-dimethoxy tetraline hydrochloride
(ST 580)
Preparation of 2-N-tyrosyl-6,7-dimethoxy tetraline hydrochloride (ST 589)
ST 581, ST 580 and ST 589 were prepared as described in Example 1.
The reaction conditions and physico-chemical properties of the
intermediates of general formula II and those of the compounds of general
formula I' are illustrated in tables 3 and 4.
TABLE 3
__________________________________________________________________________
##STR14##
M.P. .degree.C.
I step
reaction
crystallization
R.sub.1 cs time yield
solvent
NMR DMSO .delta.
__________________________________________________________________________
CH.sub.2 CH.sub.2 SCH.sub.3
2 2 h 78%
119.degree.-120.degree. C.
##STR15##
##STR16##
##STR17##
##STR18##
##STR19## 3 3 h 73%
188.degree.-190.degree. C.
##STR20##
##STR21##
##STR22## 4 3 h 90%
##STR23##
##STR24##
##STR25##
__________________________________________________________________________
TABLE 4
__________________________________________________________________________
##STR26##
M.P. .degree.C.
reaction
crystallization
R.sub.1 Es time yield
solvent NMR DMSO .delta.
__________________________________________________________________________
CH.sub.2 CH.sub.2 SCH.sub.3
2 ST 581
6.5 h
75%
96.degree.-99.degree. C. CH.sub.3 CN/ET.sub.2
##STR27##
##STR28##
##STR29##
##STR30## 3 ST 580
3 h 97%
148.degree.-149.degree. C.
##STR31##
##STR32##
##STR33## 4 ST 589
3 h 87%
dec. CH.sub.3 CN
##STR34##
##STR35##
__________________________________________________________________________
EXAMPLE 5
Preparation of 2-(N-leucylalanyl)amino-6,7-dimethoxy tetraline
hydrochloride (ST 584)
1st Step: Preparation of N-carbotertbutoxy-leucylalanine ethyl ester
Triethylamine (1.4 ml; 0.001 moles) was added to carbotertbutoxy-L-leucine
(2.5 g; 0.001 moles) dissolved in acetonitrile (50 ml).
Isobutyl chloroformate (1.3 ml; 0.001 moles) was added to the cooled
solution under stirring at -15.degree. C.
A solution of L-alanine ethyl ester hydrochloride (1.54 g; 0.001 moles) in
20 ml of acetonitrile and triethylamine (1.4 ml; 0.001 moles), prepared
separately, was added to the mixture after 1 hour under stirring at
-15.degree. C.
The reaction mixture was kept under stirring at -15.degree. C. for 2 hours
and at room temperature for 4 hours, subsequently filtered and the
filtrate concentrated under vacuum.
The residue thus obtained was taken up with ethyl acetate.
The precipitated triethylamine hydrochloride was filtered off and the ethyl
acetate solution was extracted with diluted HCl, a saturated solution of
NaHCO.sub.3 and then with H2O till neutrality was reached.
The organic phase was separated and dried on anhydrous Na.sub.2 SO.sub.4
and concentrated under vacuum. 2.35 g of a solid residue was thus
obtained. M.P. 98.degree.-100.degree. C.
##STR36##
2nd Step: Preparation of N-carbotertbutoxy-leucylalanine
6 ml of 1N NaOH were added to a solution N-carbotertbutoxy-leucylalanine
ethyl ester (1 g; 0.003 moles) dissolved in 7 ml of methanol.
The reaction mixture was kept at room temperature for 2 hours and then
dried. The residue was dissolved in a mixture of H.sub.2 O and ethyl
acetate.
The separated and dried organic phase was concentrated under vacuum. Yield
0.6 g; M.P. 73.degree. C.
##STR37##
TLC: silica gel; eluant ethyl acetate-methanol (80-20) R.F.=0.3
3rd Step: Preparation of
2-(N-carbotertbutoxy-leucylalanyl)amino-6,7-dimethoxy tetraline
hydrochloride
A solution of N-carbotertbutoxyleucylalanine (0.9 g; 0.003 moles) in 20 ml
acetonitrile was added to a solution of 2-amino-6,7-dimethoxy tetraline
(0.7 g; 0.003 moles) in 20 ml acetonitrile.
Dicyclohexylcarbodiimide (0.6 g; 0.003 moles) in 10 ml acetonitrile was
added to the solution thus obtained.
The reaction mixture was kept under stirring at room temperature for 4
hours, then filtered and the filtrate was concentrated under vacuum. The
residue thus obtained was dissolved with ethyl acetate.
The solution was extracted with a saturated solution of NaHCO.sub.3,
H.sub.2 O, diluted HCl and H.sub.2 O.
The separated and dried organic phase was concentrated under vacuum. An
oily residue was thus obtained, yield 0.4 g.
##STR38##
TLC: silica gel; eluant ethyl acetate-methanol (80-20) R.F=0.8
4th Step: Preparation of 2-(N-leucylalanyl)amino-6,7-dimethoxy tetraline
hydrochloride (ST 584)
2-(N-carbotertbutoxy-leucylalanyl)amino-6,7-dimethoxy tetraline (6.5 g;
0.01 moles) was dissolved in 36 cc trifluoroacetic acid and the solution
was kept under stirring at room temperature for 30 minutes. To the
solution ethyl ether was added, the solid thus obtained was separated by
decantation and washed several times with ethyl ether. The residue
dissolved in methanol was eluted on strong basic resin Amberlist A26
column activated in OH.sup.- form. To the eluted methanol solution HCl in
isopropanol was added until pH 3 was reached, the hydrochloride product
was precipitated with ethyl ether. The solid thus obtained was separated
by filtration furnishing 1,5 g. M.P. 85.degree.-86.degree. C.
TLC: silica gel; eluant ethyl acetate-methanol (80-20) R.F.=0.3
##STR39##
EXAMPLE 6
Preparation of 2-(N-triptophylalanyl)amino-6,7-dimethoxy tetraline
hydrochloride (ST 585)
1st Step: Preparation of N-carbotertbutoxy-triptophylalanyl ethyl ester
L-alanine ethyl ester hydrochloride (2.5 g; 0.016 moles) was dissolved in
100 ml acetonitrile.
Triethylamine (2.3 g; 0.016 moles), carbotertbutoxy L-triptophane (5.0 g;
0.016 moles) and dicyclohexylcarbodiimide (3.4 g; 0.016 moles) were added
to the solution.
The mixture was kept at room temperature overnight under magnetic stirring.
The solution was then filtered to remove dicycloesylurea that formed and
concentrated under vacuum. The residue was taken up with ethyl acetate,
the solution was filtered and subsequently extracted with a saturated
solution of NaHCO.sub.3, diluted HCl and then with H.sub.2 O. The organic
phase, separated and dried on anhydrous Na.sub.2 SO.sub.4, was
concentrated to dryness. 6 g of the product were obtained.
TLC: silica gel; eluant: ethyl acetate-methanol (60-40) R.F.=0.8
##STR40##
2nd Step: Preparation of N-carbotertbutoxytryptophylalanine
The product was obtained as described in step 2 of Example 5.
M.P.. 112.degree. C.
TLC: silica gel; eluant ethyl acetate-methanol (60-40) R.F.=0.5
3rd Step: Preparation of
2-(N-carbotertbutoxy-tryptophylalanyl)amino-6,7-dimethoxy tetraline
The product was obtained as described in step 3 of Example 5.
TLC: silica gel; eluant ethyl acetate-hexane (80-20) R.F. 0.4
##STR41##
4th Step: Preparation of 2-(N-tryptophylalanyl)amino-6,7-dimethoxy
tetraline hydrochloride (ST 585)
The product was prepared as described in step 4 of Example 5.
TLC: silica gel; eluant ethyl acetate-methanol (80-20) R.F. 0.3
E.A. C.sub.26 H.sub.33 ClNO.sub.4, 3.2% H.sub.2 O
##STR42##
The compounds:
2-(N-methionylalanyl)amino-6,7-dimethoxy tetraline hydrochloride (ST 586);
2-(N-ethyl,N-methionylalanyl)amino-6,7-dimethoxy tetraline hydrochloride
(ST 606);
2-(N-ethyl,N-tryptophylalanyl)amino-6,7-dimethoxy tetraline hydrochloride
(ST 604);
2-(N-tyrosylalanyl)amino-6,7-dimethoxy tetraline hydrochloride (ST 605)
were prepared as described in Example 6.
In particular the products ST 604 and ST 606 were obtained (4th step) by
condensing the suitable N-Boc dipeptite with
2-(N-ethyl)amine-6,7-dimethoxy tetraline prepared as described in Example
6 of the Italian patent application 48779 A/86.
The working conditions and physico-chemical data of the compounds are
described in table 5.
TABLE 5
__________________________________________________________________________
E. yield
M.P. .degree.C.
E.A. NMR .delta.
__________________________________________________________________________
E.7 ST 586
74%
hygroscopic
calc. C % 58.65; H % 7.63 N % 10.26; S % 7.83 found C %
58.86; H % 7.68 N % 10.03; S % 7.65
##STR43##
##STR44##
E.8 ST 604
58%
170.degree. C.
calc. C % 64.25; H % 7.06; N % 10.33; Cl % 6.54 found C %
61.44; H % 7.35; N % 9.78; Cl % 6.42 H.sub.2 O
##STR45##
##STR46##
E.9 ST 606
89%
118.degree.-120.degree. C.
calc C % 55.74; H % 7.65; H % 8.86; Cl % 7.48; S % 6.76
found C % 53.80; H % 7.42; N % 8.90; Cl % 7.45; S % 6.61
H.sub.2 O 3.6%
##STR47##
##STR48##
E.10 ST 605
50%
155.degree.-158.degree. C.
calc. C % 60.30; H % 6.74 N % 8.70 found C % 56.14; H %
6.53 N % 7.90 H.sub.2 O 2.85%
##STR49##
##STR50##
__________________________________________________________________________
The low toxicity and the potent antihypertensive activity of the compounds
of the present invention were assessed via several tests. The methods
employed and the results of some of these tests are illustrated
hereinbelow.
Toxicological Tests
(a) Tolerability
Male albino Swiss mice weighing 22-24 g were used in this test.
One group of animals (4/dose) which had been kept fasting for 18 hours was
orally administered the compounds dissolved in twice distilled water. The
same compounds dissolved in saline at pH=7 were intravenously injected in
a further group of animals which had free access to food and drinking
water. All of the animals were monitored for 7 days.
The test results are reported in the first column of table 7.
(b) LD50
LD50 was assessed according to the Carrol S. WEIL's method (Biometrics,
pages 249-163 (1952)) on male Albino Swiss mice weighing 22-24 g. The
compounds dissolved in 9% saline solution were administered via the
intravenous route. The results are illustrated in table 6.
TABLE 6
______________________________________
Compound LD50 mg/kg from mg/kg to mg/kg
______________________________________
ST 580 66.67 60.44 73.53
ST 581 74.03 65.58 83.57
ST 582 72.29 72.29 72.29
ST 584 167.04 153.96 181.23
ST 585 115.20 106.18 124.98
ST 586 228.87 240.18 347.43
ST 589 217.84 195.40 242.86
ST 604 85.01 77.08 93.76
ST 605 72.29 72.29 72.29
ST 606 150.41 136.37 165.90
______________________________________
Pharmacological Tests
(a) Measure of arterial pressure in cats.
Normotensive cats of either sex weighing 2.5-3.5 kgs were used in this
test.
The animals fasted for 18 hours were anesthetized with Na Nembutal (30
mg/kg) and ethyl urethane (300 mg/kg i.p.). The crural vein and artery of
the animals were cannulated, the former for administering the compounds,
the latter for monitoring the arterial pressure. The arterial pressure was
measured via a mercury gauge connected to a rotating kymograph.
The compounds were dissolved in sterile 0.9% saline and administered at
physiological pH in a 0.5 ml/kg volume.
The results are illustrated in the second column of table 7.
(b) Non-invasive measure of arterial pressure in genetically hypertensive
rats.
Male SHR rats (Charles River) of 3-4 months were used in this test. The
compounds listed were dissolved in either 0.9% saline or twice distilled
water and administered via the oral route or i.p. (50-100 mg/5 ml/kg).
The animals, housed in individual cages at 23.degree. C. and 60% humidity,
had free access to food and drinking water. A BP recorder (Letica)
equipped with a two-way polygraph was used. The systolic and diastolic
pressure and the heart rate were recorded. The animals, a few days before
the test began, were accustomed to be constrained on a heating plate (at
38.degree. C..+-.1.degree. C.) for 20 minutes).
During the pre-tests, the assessments were made at time 0 (8.sup.30
-9.sup.30 a.m.) and after 1, 2 and 4 hours.
Every assessment was the average of 3 measures and the maximum residence
time of the animal in the thermostatized chamber (for the whole test
duration) was 40 minutes.
Student's "t" test was used for assessing the difference with respect to
the control group and its own 0 time.
The results are shown in the third column of table 7.
TABLE 7
__________________________________________________________________________
II
HYPOTENSIVE EFFECT
III
I IN NORMOTENSIVE CATS
ANTIHYPERTENSIVE EFFECT IN
TOLERABILITY dose mg/kg SHR HYPERTENSIVE RATS
dose mg/kg hypotension mm Hg
COMPOUNDS
os e.p.
mm Hg doses mg/kg
1.sup.st h
2.sup.nd h
4.sup.th h
__________________________________________________________________________
ST 580 >50
>50
1-4 mg 0 -- -- -- --
ST 581 " " 1-4 mg 0 -- -- -- --
ST 582 " " 10 mg -12S 50 i.p.
-37
-27 0
20 mg -66L
ST 584 " " 4 mg -20A 10C
os -12
0 0
ST 585 " " 4 mg 0 -- -- -- --
10 mg -46S
ST 586 " " 2 mg 0 -- -- -- --
4 mg -14S
ST 589 " " 1 mg -10S 100
os -26
-20 0
2 mg -14S
4 mg -60L
ST 604 " " 1-4 mg 0 -- -- -- --
ST 605 " " 1 mg 0 100
e.p.
-40
-38 -29
2 mg -10S 100
os -28*
-31*
4 mg -14A -- -35**
-17**
ST 606 " " 1 mg -10S -- -- -- --
2 mg -12S
4 mg -18S
__________________________________________________________________________
EFFECT DURATION:
S = short
A = average
L = long
ADMINISTRATION ROUTES:
os = oral
i.p. = intraperitoneal
i.v. = intravenous
*single administration
**repeated administration (5 days).
The dose of the compounds of formula (I) to be administered will be
determined having regard to the age, weight and general conditions of the
patient. Effective results can be obtained with doses of about 0.5-5 mg/kg
body wight/day. Because of the low toxicity of the compounds of the
present invention larger doses can be administered, such as 8-10 mg/kg
body weight/day.
The compounds of the present invention can be formulated by procedures
well-known to those skilled in the pharmaceutical technology into the
usual administration forms which comprise orally or parenterally
administrable solid and liquid unit dosage forms. These unit dosage forms
comprise from about 20 to about 50 mg of the active principle, in addition
to the usual excipients.
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